B7-CD28 co-stimulation enforces central tolerance by thymic clonal deletion and Treg cell generation through distinct mechanisms

Abstract

Abstract To establish central T cell tolerance in the thymus, thymocytes expressing TCR strongly reactive to self-Ag-MHC complex are eliminated from the conventional T cell (Tconv) repertoire by two distinct processes, clonal deletion or clonal diversion to non-conventional T cell lineages such as Foxp3+ regulatory T (Treg) cells. We analyzed the requirements for B7-CD28 co-stimulation for thymic clonal deletion and Treg cell generation of endogenous tissue-restricted-antigen (TRA)-specific thymocytes. We found that: 1) both clonal deletion and Treg cell generation of TRA-specific thymocytes were B7-CD28-dependent, and that clonal deletion had a greater effect than Treg diversion in eliminating TRA-specific T cells from the Tconv repertoire; 2) B7-expressing APC requirements differed for clonal deletion and Treg generation; and 3) although B7-CD28 mediated both clonal deletion and Treg cell generation, CD28 cytoplasmic domain requirements for these two processes were different. These results indicate that qualitatively distinct CD28 signaling determines fates of strongly self-reactive thymocytes. To further characterize the CD28 signaling pathways involved in clonal deletion and Treg cell generation, single cell transcriptomic analyses of TRA-specific thymocyte are underway.